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Patent Nov. 4, I924.

-HORACE A. SHONLE, OF INDIA NAPO'LIS, INDIANA, ASSIGNOR TO THE ELI LILLY& COMPANY, OF INDIANAPOLIS, INDIANA, A CORPORATION OF INDIANA.

' ISOL ETHYL BARBITURIC ACID.

No Drawing.

T all whom it may concern:

Be it known that I, HORACE A. Sammie, a citizen of the United States,residing at Indianapolis, in the county of Marion and a State of Indianahave invented a new and useful Isoamyl Eth l Barbituric Acid, of whichthe following is a specification.

\ My invention has for its object the obtaining of a substance whichpossesses marked hypnotic activity combined with low toxicity, andrelates to the production of the hitherto unknown hypnotic substance,isoamyl ethyl barbituric acid or isoamyl ethyl malonyl urea. V

Isoamyl ethyl barbituric acid exhibits pronounced g soporific orhypnotic properties, and at the same time'has such a low toxicity thatthe ratio of the, toxic dose to the efi'ective hypnotic dose is muchgreater than in the case of any of the previousl known hypnotics of asimilar character, t us afiordm a greater factor of safety. This factor0 safety is even greater than in the case of isobutyl ethyl barbitunicacid, for which I 2 have filed'an applicatlon for a Patent Serial No.454,149 of even filing date herewith. This isoamyl ethyl barbituric acidcauses no ataxia but produces a. quiet sleep with no disagreeable aftereffects.-

The new isoamyl ethyl barbituric acid possesses thestructure om-cn, c0-NH\ cn-c1n0m c o-NH OH:

in which one of the hydrogen atoms attached to a nitrogen atom can bereplaced by a monovalent metal, such, for instance, as

i sodium, or by an equivalent of a polyvalent metal, such, for instance,as calcium.

The new is'oamyl ethyl barbituric acid may be produced by variousprocesses. One of these consists in condensing urea with isoamyl ethylmalonic ester in the resence of sodium ethylate, using substantially thefollowing quantities, temperatures, and periods of tlme, although theproduct may still be obtained in varying yields even if these factorsare changed 261 grams (3 moles) of metallic sodium are dissolved in 500hol, to which are ad ed 100 grams (1 mole) of isoamyl ethyl malonicester and 37.2 grams (1.6 mole) of urea. This mixture is ams of absolutealco-' llpplicatioi filed March 21, 1921. Serial No. 454,150.

heated in an enameled autoclave for 4 to 6 hours at a temperature ofabout 105 C. The isoamyl ethyl barbituric acid formed by thiscondensation is present as its sodium salt. The mixture isthen acidifiedwith hydrocholoric acid and the alcohol removed by distillation. Thecrude isoamyl ethyl barbituric acid remains as a residue in thedistilling flask.

This crude isoamyl ethyl barbituric acid upon re-crystallization fromwater is obtained in the form of white crystals, which melt at. 153-155O. The re-crystallized substance is slightly soluble in cold water,

more soluble in hot water, and easily soluble in alcohol and ether,and-has a slightly bitter taste.

Since isoamyl. ethyl barbituric acid possesses one nitrogen-linkedhydrogen capable of being replaced with a monovalent metal, such assodium, or-with an equivalent of a polyvalent metal, it is possible toform metallic salts of this acid. The acid and the metallic salts may berepresented by the following formula:

in which X represents either a hydrogen atom and' somewhat less solublein absolute alco hol. The soluble salts are of value for hypodermicinjection.

I claim as my invention: 1. The new substances, which may be representedby the formula:

out-on co-NH CH wherein X represents either a hydrogen atom, an atom ofa monovalent metal, or an equivalent of a olyvalent metal.

2. The new su stance, isoamyl ethyl barbituric acid, being a compounddisplaying a hypnotic action, crystallizing from water in the form ofWhite crystals melting at 153- 155 0., being slightly soluble in coldwater, more soluble in hot water, easily soluble in alcohol and ether,having a slightly bitter taste, and forming with the alkali metals saltswhich are readily soluble in Water.

3. The new substances, which contain the radicle which may berepresented by the formula:

4. As a new product isoamyl ethyl barb i turic acid having the formula:

In witness whereof, I have hereunto set v my hand at Indianapolis,Indiana, this 17th day of March, A. D. one thousand nine hun- 20 dredand twenty .one.

HORACE A. SHONLE.

